Abstract
ABSTRACTSkeletal myogenesis in vertebrates is initiated at different sites of skeletal muscle formation during development, by activation of specific control elements of the myogenic regulatory genes. In the mouse embryo, Myf5 is the first myogenic determination gene to be expressed and its spatiotemporal regulation requires multiple enhancer sequences, extending over 120 kb upstream of the Mrf4-Myf5 locus. An enhancer, located at −57/−58 kb from Myf5, is responsible for its activation in myogenic cells derived from the hypaxial domain of the somite, that will form limb muscles. Pax3 and Six1/4 transcription factors are essential activators of this enhancer, acting on a 145-bp core element. Myogenic progenitor cells that will form the future muscle masses of the limbs express the factors necessary for Myf5 activation when they delaminate from the hypaxial dermomyotome and migrate into the forelimb bud, however they do not activate Myf5 and the myogenic programme until they have populated the prospective muscle masses. We show that Msx1 and Meox2 homeodomain-containing transcription factors bind in vitro and in vivo to specific sites in the 145-bp element, and are implicated in fine-tuning activation of Myf5 in the forelimb. Msx1, when bound between Pax and Six sites, prevents the binding of these key activators, thus inhibiting transcription of Myf5 and consequent premature myogenic differentiation. Meox2 is required for Myf5 activation at the onset of myogenesis via direct binding to other homeodomain sites in this sequence. Thus, these homeodomain factors, acting in addition to Pax3 and Six1/4, fine-tune the entry of progenitor cells into myogenesis at early stages of forelimb development.
Highlights
The Myf5 myogenic determination gene is not activated in limb muscle progenitor cells when they delaminate from the somite and migrate to the limb bud, despite expression of Pax3 and Six1/4 which can activate the Myf5 limb regulatory element
We show that direct binding of Msx1 and Meox2 controls the precise onset of Myf5 activation in the forelimb bud in vivo
We found that the delay of Myf5 activation in Meox2 mutants, occurring via the 145-bp element, is compensated in forelimbs by E12.5 and no difference in Myosin Heavy Chain expression was observed in Meox2 mutant limbs (B.S.M., unpublished)
Summary
Skeletal muscles in the trunk and limbs derive from myogenic progenitor cells present in the somites of the vertebrate embryo and their formation depends on myogenic regulatory factors controlling. Thereafter, MyoD is expressed and can direct cells into the myogenic programme when Myf and Mrf are absent (Braun et al, 1992) The absence of these three myogenic determination factors leads to the absence of skeletal muscles (Kassar-Duchossoy et al, 2004; Rudnicki et al, 1993). Skeletal muscle in the limbs is formed by muscle progenitor cells that delaminate from the hypaxial dermomyotome of the somites and migrate into the limb field These cells express the paired/ homeodomain transcription factor Pax and in its absence they fail to migrate and subsequently undergo apoptosis (see Buckingham and Relaix, 2007). In the absence of Six1/4, limb muscles do not form correctly and Pax expression in the hypaxial somite is compromised (Grifone et al, 2005)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
